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Meta-Analysis
. 2023 Jul 3;6(7):e2325914.
doi: 10.1001/jamanetworkopen.2023.25914.

Biomarkers Associated With Severe COVID-19 Among Populations With High Cardiometabolic Risk: A 2-Sample Mendelian Randomization Study

Tushar Sood  1   2 , Nicolas Perrot  1   3   4 , Michael Chong  1   3   4 , Pedrum Mohammadi-Shemirani  1   3   4   5 , Maha Mushtaha  1 , Darryl Leong  1   6 , Sumathy Rangarajan  1 , Sibylle Hess  7 , Salim Yusuf  1   6 , Hertzel C Gerstein  1   6 , Guillaume Paré  1   3   4 , Marie Pigeyre  1   6
Affiliations
Meta-Analysis

Biomarkers Associated With Severe COVID-19 Among Populations With High Cardiometabolic Risk: A 2-Sample Mendelian Randomization Study

Tushar Sood et al. JAMA Netw Open. .

Abstract

Importance: Cardiometabolic parameters are established risk factors for COVID-19 severity. The identification of causal or protective biomarkers for COVID-19 severity may facilitate the development of novel therapies.

Objective: To identify protein biomarkers that promote or reduce COVID-19 severity and that mediate the association of cardiometabolic risk factors with COVID-19 severity.

Design, setting, and participants: This genetic association study using 2-sample mendelian randomization (MR) was conducted in 2022 to investigate associations among cardiometabolic risk factors, circulating biomarkers, and COVID-19 hospitalization. Inputs for MR included genetic and proteomic data from 4147 participants with dysglycemia and cardiovascular risk factors collected through the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial. Genome-wide association study summary statistics were obtained from (1) 3 additional independent plasma proteome studies, (2) genetic consortia for selected cardiometabolic risk factors (including body mass index [BMI], type 2 diabetes, type 1 diabetes, and systolic blood pressure; all n >10 000), and (3) the COVID-19 Host Genetics Initiative (n = 5773 hospitalized and 15 497 nonhospitalized case participants with COVID-19). Data analysis was performed in July 2022.

Exposures: Genetically determined concentrations of 235 circulating proteins assayed with a multiplex biomarker panel from the ORIGIN trial for the initial analysis.

Main outcomes and measures: Hospitalization status of individuals from the COVID-19 Host Genetics Initiative with a positive COVID-19 test result.

Results: Among 235 biomarkers tested in samples totaling 22 101 individuals, MR analysis showed that higher kidney injury molecule-1 (KIM-1) levels reduced the likelihood of COVID-19 hospitalization (odds ratio [OR] per SD increase in KIM-1 levels, 0.86 [95% CI, 0.79-0.93]). A meta-analysis validated the protective association with no observed directional pleiotropy (OR per SD increase in KIM-1 levels, 0.91 [95% CI, 0.88-0.95]). Of the cardiometabolic risk factors studied, only BMI was associated with KIM-1 levels (0.17 SD increase in biomarker level per 1 kg/m2 [95% CI, 0.08-0.26]) and COVID-19 hospitalization (OR per 1-SD biomarker level, 1.33 [95% CI, 1.18-1.50]). Multivariable MR analysis also revealed that KIM-1 partially mitigated the association of BMI with COVID-19 hospitalization, reducing it by 10 percentage points (OR adjusted for KIM-1 level per 1 kg/m2, 1.23 [95% CI, 1.06-1.43]).

Conclusions and relevance: In this genetic association study, KIM-1 was identified as a potential mitigator of COVID-19 severity, possibly attenuating the increased risk of COVID-19 hospitalization among individuals with high BMI. Further studies are required to better understand the underlying biological mechanisms.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Mohammadi-Shemirani reported being employed by Deep Genomics Inc during the conduct of the study. Dr Hess reported being employed by and holding shares in Sanofi during the conduct of the study. Dr Gerstein reported receiving grants from Sanofi for the ORIGIN trial during the conduct of the study. Dr Gerstein also reported receiving grants from Sanofi, Novo Nordisk, and Eli Lilly; personal fees from Sanofi and Novo Nordisk for advisory board service; speaker honoraria from Eli Lilly, AstraZeneca, DKSH, Zuellig, and Jiangsu Hansoh Pharmaceutical; and consulting fees from Kowa, Hanmi, and Boehringer Ingelheim outside the submitted work. Dr Paré reported receiving grants from Bayer during the conduct of the study. Dr Paré also reported receiving personal fees from Bayer, Amgen, Novartis, and Illumina outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Associations Among Body Mass Index (BMI), Kidney Injury Molecule-1 (KIM-1), and COVID-19 Hospitalization
Two-sample mendelian randomization (MR) analysis of associations between BMI and KIM-1, KIM-1 and COVID-19 hospitalization, and BMI and COVID-19 hospitalization. Multivariable MR analysis of the association between BMI and COVID-19 hospitalization, with KIM-1 as a covariate. Odds ratios (ORs) are presented with 95% CIs and P values.
See this image and copyright information in PMC

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